Myasthenia gravis (MG), which is by far the most common clinical disorder of the neuromuscular junction, is due to an antibody-mediated autoimmune attack against acetylcholine receptors (AChRs). The major challenge in MG is to use the detailed knowledge of its pathogenesis to design immunotherapeutic strategies that will a) specifically eliminate the anti-AChR autoimmune responses; b) have long-lasting effects, and c) eventually be applicalbe to human MG: We will develop and test a series of novel strategies for specific immunotherapy in the experimental model of myasthenia gravis in the rat (EAMG). 1) We will induce and propagate AChR-specific suppressor T lymphocytes, using two approaches that have already been successful in preliminary experiments in our hands: a) incubation with lymphocytes from EAMG rats with Cyclosporin A (CsA) plus AChR in vitro, b) incubation of lymphocytes from EAMG rats syngeneic lymphocytes with covalently coupled AChR. The suppressor cells induced by these methods, or soluble suppressor factors produced by them, will first be tested in a cell culture system, and then will be used to treat rats with EAMG. 2) We will attempt to treat EAMG by immunizing rats with a pure population of AChR-sensitized lymphoblasts. This method induces a powerful and broad spectrum anti-idiotypic reaction that should down-regulate the anti-AChR immune response. 3) We will use the promising method of "total lymphoid irradiation" (TLI) to attempt to induce long lasting and specific suppression of the anti-AChR response in animals with EAMG. ULtimately, the mehtods developed in this model system should be applicable to the treatment of human MG, and other autoimmune neuromuscular disorders.